Prolactin Potentiates Transforming Growth Factor α Induction of Mammary Neoplasia in Transgenic Mice

Abstract

Prolactin influences mammary development and carcinogenesis through endocrine and autocrine/paracrine mechanisms. In virgin female mice, pro-lactin overexpression under control of a mammary selective nonhormonally responsive promoter, neu-related lipocalin, results in estrogen receptor alpha (ERalpha)-positive and ERalpha-negative adenocarcinomas. However, disease in vivo occurs in the context of dysregulation of multiple pathways. In this study, we investigated the ability of prolactin to modulate carcinogenesis when co-expressed with the potent oncogene transforming growth factor alpha (TGFalpha) in bitransgenic mice. Prolactin and TGFalpha cooperated to reduce dramatically the latency of mammary macrocyst development, the principal lesion type induced by TGFalpha. In combination, prolactin and TGFalpha also increased the incidence and reduced the latency of other preneoplastic lesions and increased cellular turnover in structurally normal alveoli and ducts compared with single transgenic females. Bitransgenic glands contained higher levels of phosphorylated ERK1/2 compared with single TGFalpha transgenic glands, suggesting that this kinase may be a point of signaling crosstalk. Furthermore, transgenic prolactin also reversed the decrease in ERalpha induced by neu-related lipocalin-TGFalpha. Our findings demonstrate that locally produced prolactin can strikingly potentiate the carcinogenic actions of another oncogene and modify ovarian hormone responsiveness, suggesting that prolactin signaling may be a potential therapeutic target.

Estrogen receptor-positive mammary tumorigenesis in TGFα transgenic mice progresses with progesterone receptor loss

“…Recent findings revealing distinctive molecular profiles for ERÀ tumors containing ErbB1 versus ErbB2 (Creighton et al, 2006) may shed light on these differences. Cystic papillary tumors in NRL-TGFa mice resemble those of other TGFa transgenic mice (Humphreys and Hennighausen, 2000;Rose-Hellekant and Sandgren, 2000;Arendt et al, 2006). Concurrent expression of heterozygous p53 results in aggressive solid tumors of varying types reflecting the tumor spectrum of p53 þ /À BALB/c mice (Blackburn et al, 2003;Jerry et al, 2000;Kuperwasser et al, 2000), although relative proportions cannot be determined due to low numbers of p53 þ /À mice in the present study.…”

Prolactin Drives Estrogen Receptor-α-Dependent Ductal Expansion and Synergizes with Transforming Growth Factor-α to Induce Mammary Tumors in Males

“…16,17 Transgenic virgin female mice that overexpress TGF-␣ under control of the NRL promoter develop mammary tumors and preneoplastic lesions. 18,19 Together, TGF-␣ and PRL potently cooperate; bitransgenic NRL-TGF-␣/PRL females develop mammary tumors similar to those found in NRL-TGF-␣ females with a greatly reduced latency and 100% incidence. 18 This hormone/growth factor interaction is also strongly oncogenic in the male.…”

“…18,19 Together, TGF-␣ and PRL potently cooperate; bitransgenic NRL-TGF-␣/PRL females develop mammary tumors similar to those found in NRL-TGF-␣ females with a greatly reduced latency and 100% incidence. 18 This hormone/growth factor interaction is also strongly oncogenic in the male. Bitransgenic NRL-TGF-␣/PRL males developed mammary tumors with similar incidence and latency to that found in NRL-TGF-␣/PRL females 18 ; single transgenic males developed no lesions.…”

“…18 This hormone/growth factor interaction is also strongly oncogenic in the male. Bitransgenic NRL-TGF-␣/PRL males developed mammary tumors with similar incidence and latency to that found in NRL-TGF-␣/PRL females 18 ; single transgenic males developed no lesions. Like male breast cancer in humans, the resulting tumors expressed variable levels of both ER-␣ and AR.…”

“…This novel model system offers important insight into PRL, ER-␣, and TGF-␣ interactions in the pathogenesis of this disease in males and suggests therapeutic targets that may enhance survival in male breast cancer. 18,19 were generated as described. All lines were maintained in the FVB/N strain background.…”